Substituted 1,4-benzodioxanes

ABSTRACT

THE INVENTION PROVIDES BASICALLY 2-SUBSTITUTED 1,4-BENZODIOXANES HVAING THE GENERAL FORMULA:   2-(R1-SO2-(CH2)N-NH-CH2-),R-1,4-BENZODIOXANE   WHERE R IS A HYDROGEN ATOM, A HALOGEN ATOM HAVING AN ATOMIC NUMBER NOT EXCEEDING 35 OR AN ALKYL OR ALKOXY GROUP HAVING FROM ONE TO SIX CARBON ATOMS, R1 IS A SATURATED ALIPHATIC GROUP HAVING ONE TO EIGHT CARBON ATOMS, AND N IS AN INTEGER FROM 2 TO 6 AND ACID ADDITION SALTS OF SUCH BENZODIOXANES. THE COMPOUNDS ENCHIBIT AN UNUSUSAL COMBINATION OF TRANQUILISING, TAMING AND AGGRESSION-BUILDING ACTIVITY WHEN ADMINISTERED TO RATS.

United States Patent 3,755,367 SUBSTITUTED 1,4-BENZODIOXANES PeterNichol! Green, Liverpool, and Maurice Shapero, Edgeware, England,assignors to Ward Blenkmsop & Company Limited, Wemhley, England NoDrawing. Filed Sept. 24, 1971, Ser. No. 183,684 Claims priority,application Great Britain, Sept. 24, 1970, 45,671/70 Int. Cl. C07d 15/12US. Cl. 260-3403 6 Claims ABSTRACT OF THE DISCLOSURE The inventionprovides basically Z-substituted 1,4-benzodioxanes having the generalformula:

where R is a hydrogen atom, a halogen atom having an atomic number notexceeding 35 or an alkyl or alkoxy group having from one to six carbonatoms,

R is a saturated aliphatic group having one to eight carbon atoms, and

n is an integer from 2 to 6 and acid addition salts of suchbenzodioxanes. The compounds exhibit an unusual combination oftranquilising, taming and aggression-building activity when administered10 rats.

This invention relates to the production of pharmacologically valuable1,4-benzodioxanes.

The present invention provides a basically 2-substituted1,4-benzodioxane having the general formula:

NH H .R I O CHz (C 2) S02 (1) in which R is a hydrogen atom, a halogenatom having an atomic number not exceeding 35 or an alkyl or alkoxygroup having one to six, preferably one or two, carbon atoms, R is asaturated aliphatic group having one to eight, preferably two to six,carbon atoms and n is an integer from Q, to 6, and acid addition saltsof such benzodioxanes.

The substituent R may be present in any of the four available positionsin the benzene ring of the '1,4-benzodioxane nucleus, i.e., in the 5-,6-, 7- or 8-position. The group R may be, for example, chlorine,bromine, methyl, ethyl, methoxy or ethoxy, but is most preferablyhydrogen.

The acid addition salt may be any pharmacologically acceptable salt, forexample, the hydrochloride, hydrobromide, sulphate, phosphate, acidmaleate, acid succinate, acid tartrate or lactate of the said1,4-benzodioxanes.

The substituent R may be an alkyl group having one to eight, preferablytWo to six, carbon atoms and may be a straight chain orbranched chainalkyl group. When it is a branched chain alkyl group it may beatertiary-alkyl group. Examples of suitable alkyl groups are methylethyl, isopropyl, n-butyl, isobutyl, secondary-butyl, tertiary-butyl,secondary-amyl, tertiary-amyl, n-hexyl, 2,2-dimethyl-nbutyl,3,3-dimthyl-n-propy1, tertiary-heptyl and tertiaryoctyl. Alternatively Rmay be a cycloalkyl group, for example a cyclohexyl group.

The group (CH is a'polymethylene group containing not more than sixcarbon atoms: it is preferred that this group consist of two, threeorfour methylene groups.

According to a feature of the invention basically substi- 3,755,367Patented Aug. 28, 1973 with a mono-substituted alkyl sulphone having thegeneral formula in which formulae R, R and n are as above-defined, oneof X and Z is a halogen atom and the other is a primary amino group.

Thus the reaction may be between a Z-aminomethyl- 1,4-benz-odioxane anda straight chain omega-haloalkyl sulphone in which the second organicgroup attached to sulphur is a saturated aliph'atic group having 1 to 8carbon atoms, or between a 2-halomethyl-1,4-benzodioxane and a straightchain omega-aminoalkyl sulphone in which the second organic groupattached to sulphur is a saturated aliphatic group having 1 to 8 carbonatoms. Both of these reactions lead to the formation of a hydrohalide ofthe 2-substituted 1,4-benzodioxane. This hydrohalide may be subsequentlydecomposed by treating the crude product with an acid acceptor. It ispreferred to use an inorganic acid acceptor and to carry out thereaction in the presence of a solvent for the base being liberated.After separation of the organic phase containing the free sulphone base,solvent and any low boiling volatile materials can be removed therefrom,the residue taken up in a volatile solvent and treated with a solutionof an acid in order to form the corresponding salt.

The Z-aminomethyl-l,4-benzodioxane from which the compounds of thepresent invention may be obtained includeZ-aminomethyl-1,4-benzodioxane, 2-aminomethyl-7-chloro-1,4-benzodioxane,Z-aminomethyl-S-methyl-l,4-benzodioxane and2-aminomethyl-8-methoxy-1,4-benzodioxane.

compounds of the present invention may also be obtained includeZ-chloromethyl-1,4-benzodioxane, 2-bromomethyl-1,4-benzodioxane,2-chloromethyl-7-chloro-1,4-benzodioxane,Z-chloromethyl-S-methyl-1,4-benzodioxane andZ-chloromethyl-S-methoxy-1,4-benzodioxane.

Examples of straight chain omega-aminoalkyl sulphones which may bereacted with the 2-halomethyl-1,4-benzodioxanes includetertiary-butyl-Z-aminoethyl sulphone, methyl 3-amino-n-propyl sulphone,ethyl 3-amino-n-propy1 sulphone, iso-propyl S-amino-n-propyl sulphone,tertiarybutyl 3-amino-n-propyl sulphone, tertiary-amyl 3-aminon-propylsulphone, tertiary-butyl 4-amino-n-butyl sulphone, tertiary-butylS-amino-n-pentyl sulphone, tertiarybutyl 6-amino-n-hexyl sulphone andcyclohexyl 3-amino-npropyl sulphone.

According to an alternative feature of the invention basicallysubstituted 1,4-benzodioxanes having the first general formula givenabove may also be prepared by a process which comprises reacting asolution in an organic solvent of an acylated 2-substituted1,4-benzodioxane having the general formula:

in which R, R and n are as defined above with a miscible solution ofhydrogen peroxide in an organic organic solvent, and thereafterhydrolysing the N-acyl group with a strong acid.

The acylated Z-substituted 1,4-benzodioxanes are in turn prepared by theacylation of basically 2-substituted 1,4-benzodioxanes having thegeneral formula in which R, R and n are as above defined. Suitableacylating agents are the acid halides and anhydrides of aliphatic andaromatic monocarboxylic acids such as acetic and propionic anhydridesand benzoyl chloride.

The basically substituted 1,4-benzodioxanes having the General Formula Vmay be prepared by the reaction of a Z-monosubstituted-methyl1,4-benzodioxane having the General Formula II with a mono-substitutedalkyl sulphide having the general formula in which R Z and n are asabove defined. The preparation of such compounds in which R is ahydrogen atom or an alkoxy group is described in ED. Auslegeschrift No.1,118,218: amongst the compounds disclosed therein are 2-w-methylmercapto-n-butylaminomethyl l ,4

benzodioxane,

2- (w-methylmercapto-n-propylaminomethyl) 1 ,4-

benzodioxane,

2-(w-ethylmercapto-n-propylaminomethyl)-1,4-

benzo dioxane,

2- w-butylmercapto-n-propylaminomethyl) -1 ,4-

benzo dioxane,

5-methoxy-2- w-me thylmercapto-n-propylarninomethyl 1,4-benzodioxane,

8 -methoxy-2- w-methylmercap to-n-propylaminomethyl) 1,4-benzodioxaneand 8 ethoxy 2-(w-methylmercapto-n-propylamiuomethyl)- 1,4benzodioxane.Those compounds containing in the benzene ring of the 1,4-benzodioxanenucleus a halogen atom or an alkyl group may be prepared by analogousprocedures. When produced by this process the compounds of the inventionare conveniently obtained as the salts thereof with the acid used toeffect the deacylation.

With respect to the oxidation of the acylated 2-substituted1,4-benzodioxanes with hydrogen peroxide it is preferred to use the sameorganic solvent for both the acylated 1,4-benzodioxane and the hydrogenperoxide. The normally liquid alkane monocarboxylic acids, especiallyacetic acid, are suitable for this purpose. The oxidation is anexothermic reaction and it is therefore desirable to add the hydrogenperoxide solution over a period of time so as to prevent the temperatureof the reaction mixture exceeding a predetermined maximum of, forexample, 50 C. After completion of the reaction the resulting sulphoneis conveniently isolated by taking advantage of its solubility in anorganic solvent in which the organic solvent used to carry out thereaction is substantially insoluble, the solution freed from anyresidual hydrogen peroxide, and the produce then hydrolysed with astrong acid, conveniently after removal of the organic solvent.

The compounds of the present invention have been tested upon mice andrats and have been found to exert muscle relaxant, sedative,tranquilising and taming properties thereon.

An unusual feature of the compounds of the invention is their ability toinduce agressive behaviour in male rats 12 to 24 hours afteradministration.

At suitable dose levels, the compounds of the invention appear able toinduce in rats a characteristic combination of quietness or tameness andself-confidence in the face of aggression. This effect is howeverbiphasic, and is superseded at higher dose levels by relaxant effects.

These compounds in which R is a branched chain alkyl group and n isthree have been found to exert muscle relaxant properties in rats forwhich ED is 0.1-1.0 mg. per kilogram bodyweight when administeredsubcutaneously and 10-100 mg./kg. when administered orally. Theapproximate LD values were 400 mg. per kilogram bodyweight whenadministered subcutaneously and greater'than 400 mg. per kilogram whenadministered orally.

When administered subcutcaneously to mice muscle relaxant propertieshave been observed for the same compounds for which the ED5G value isabout 36 mg. per kilogram bodyweight and the LD value is about 285 mg.per kilogram bodyweight: the corresponding values when administeredorally being 25 mg./kg. and 400 mg./ kg; respectively.

Doses of 10, 20, 40, 60 and mgJkg. in 1% Tween 80 of the products ofExamples 1, 2/3, 8 and 9 set out below were injected into ratsintraperitoneally daily for 4 days. On the 4th day the rats were testedfor the drugs elfect on behaviour. 8 male rats were used per dose and asimilar number recevied 1% Tween 80 as a control.

A significant increase in aggressive behaviour over the controls wasfound in the groups receiving 20 mg.'/kg. (P 0.025), with the maximumeffect at 40 mg'/kg. (P 0.05). Doses greater than 80 mg./kg. depressedaggressive behaviour. The approximate acute oral and subcutaneous LD inrats is 400 mg./kg.

A single dose of 10 mg./kg. intraperitoneally in a group of ten micereduced exploratory behaviour when placed in a Y-maze. The results werestatistically significant (P 0.-02). The approximate acute oral LD is400 mg./kg.: subcutaneously it is 250 rug/kg.

A statistical test for significance between the treated rats and thecontrols was evaluated by the Mann-Whitney U-test. 5 mg/kg.intramuscularly produced muscle relaxation in the monkey. No adverseside effects were observed. 1

An unusual feature of the compounds of the invention is their ability toinduce aggressive behaviour in male rats 12 to 24 hours afteradministration.

The following examples illustrate the production of the compounds of theinvention:

EXAMPLE 1 2- (3 '-tertiary-amylsulphonyl-n-propyl) aminomethyl1-1,4-benzodioxane Z-aminomethyl-l,4-benzodioxane (26.1 g.) and3-tertiary-amylsulphonyl-n-propylchloride 16.7 g.) were heated at C. fortwo hours prior to mixing with 2 N caustic soda (40 mls.) and extractedwith chloroform (once with 20 mls. and twice with 10 mls.). Thechloroform extracts were combined and the combined extracts distilled toa final residue temperature of 220 C; at 0.05 mm. of mercury. 5 Nhydrochloric acid (55 mls.) was added to the cooled residue and themixtures refluxed whilst ethanol (16 mls.) was added, thus givinghomogeneity. After cooling, the solution was extractedwith chloroform(once with 25 mls. and twice with 10 mls.) and anhydrous diethyl other(225 mls.) added to the combined chloroform extracts. The mixture wasallowed EXAMPLE 2 2- (3 '-tertiary-butylsulphonyl-n-propyl) aminomethyl]-1,4benzodioxane Z-aminomethyl-1,4-benzodioxane (82.5 g.) and 3-tertiary butylsulphonyl-n-propylchloride (50 g.) were heated at 150 C.for 2 hours prior to mixing with 2 N caustic soda (125 mls.) and thenextracted with chloroform (oncewith 6O mls. and twice with 25 mls.). Thechloroform extracts were combined, Washed with water and distilled to afinal residue temperature of 215 C. at 0.1 mm. to give a dark brown oil.5 N hydrochloric acid (175 mls.) was added to the cooled residue and themixture refluxed with the addition of charcoal, filtered hot, cooled,scratched and allowed to stand overnight in the ice box. The crystallineproduce is filtered and the residue on the filter washed twice withcold5 N hydrochloric acid then four times with anhydrous diethyl ether.Drying under reduced pressure gave the crude hydrochloride (52.9 g.),melting point 157-160 C.

Recrystallisation from isopropyl alcohol have the product as whitecrystals, melting point 157 to 160 C.

Analysis-Calculated for C H NSClO (percent): C,

52.81; H, 7.20; N, 3.85; S, 8.81; CI, 9.74. Found (percent): C, 52.91;H, 7.00; N, 4.02; S, 9.02; Cl. 9.68.

EXAMPLE 3 2- (3 '-tertiary-butylsulphonyl-n-propyl) aminomethyl1-1,4-benzodioxane 2-(3-tertiary-butylthio n propyl)aminomethyl-1,4-benzodioxane (18.2 g.) and acetic anhydride (6.7 mls.) were heated on asteam bath under reflux for thirty minutes, the volatile materialsevolved were 'then removed under reduced pressure at 100 C. and theresidue dissolved in acetic acid (60 mls.). After cooling to roomtemperature a mixture of acetic acid (22.5 mls.) and hydrogen peroxide(22.5 mls. of 100 vol.) was added with stirring and cooling at such arate that the temperature did not exceed 50 C. The mixture was thenrefluxed for one hour prior to pouring into water (600 mls.) andextraction with chloroform (once with 50 mls. and twice with 20 mls.).The chloroform extracts were combined and then washed with water (thricewith 20 mls.)-a few drops of 20% w./w. sodium sulphite solution beingadded to the last portion of water until a negative peroxide indicationwas obtained. After removal of the chloroform under reduced pressure theresidual oil was mixed with 5 N hydrochloric acid (60 mls.) and refluxedfor nine hours. On cooling and scratching and standing overnight in theice box, crystals separated: these crystals were filtered 011 and twicewashed with cold 5 N hydrochloric acid, then four times with anhydrousdiethyl ether followed by drying under reduced pressure to give thecrude product (9 g.), melting point 153 to 156 C.

Two recrystallisations from isopropyl alcohol gave the product as thehydrochloride, melting point 157 to 160 C. Mixed melting point with theproduct of Example 2 gave no depression.

EXAMPLE 4 2- (3 -is opropylsulphonyl-n-propyl) aminomethyll ,4-benzodioxane 2-aminomethyl-1,4-benzodioxane (33 g.) and3-isopropylsulphonyl-n-propyl chloride (18.45 g.) were heated at 150 C.for 2 hours prior to working up as described, in Example 2. Drying underreduced pressure gave the crude hydrochloride (16.5 g.), melting pointto 148 C. Recrystallisation from a mixture of isopropanol (70 mls.) andethanol (20 mls.) gave the productas white crystals, melting point 148to 150 C.

Analysis.-Calculated for C H 'NSClO (percent): C, 51.48; H, 6.91; S,9.16; CI, 10.14; N, 4.00. Found (percent): C, 5l.40; H, 6.80; S, 9.27;Cl, 10.32; N, 3.78.

EXAMPLE 5 2- 3 -ethylsulphonyl-n-propyl) -aminomethyl-1,4-benzodioxane2-aminomethyl-l,4-benzodioxane (33 g.) and 3-ethylsulphonyl-n-propylchloride (17 g.) were heated at 150 C. for 2 hours prior to working upas described in Example 2. Drying under reduced pressure gave the crudehydrochloride (25.9 g.), melting point 167 to 169 C.

Recrystallisation from a mixed solvent of methanol (75 mls.), andethanol (50 mls.) gave the product as white crystals, melting point 172to 174 C.

Analysis-Calculated for C14H2qNSclO4 (percent): C, 50.07; H, 6.61; N,4.17; S, 9.55; CI, 10.56. Found (percent): C, 50.18; H, 6.63; N, 4.11;S, 9.25; CI, 10.20.

EXAMPLE 6 2-(4'-tertiary-butylsulphonyl-n-butyl)aminomethyl-1,4-benzodioxane 2-(4'-tertiary-butylthio-n-butyl)aminomethyl-1,4-benzodioxane (15.3 g.) and acetic anhydride (5.6 mls.)were reacted and worked up as described in Example 3. The acylatedcompound was then treated with hydrogen peroxide and acetic acid, thefurther treatment and working up also proceeding as described in Example3. Drying under reduced pressure gave the crude hydrochloride (7.3 g.),melting point 182 to 184C.

Recrystallisation from ethanol gave the product as white crystals,melting point 186 to 188 C.

Analysis.-Calculated for C1I7H23NSC1O4 (percent): C, 54.04; H, 7.47; N,3.71; S, 8.49; Cl, 9.38. Found (percent): C, 53.73; H, 7.49; N, 3.56; S,8.37; CI, 9.35.

EXAMPLE 7 2-(3'-cyclohexylsulphonyl-n-propyl)aminomethyl-l,4-benzodioxane i onmnomomoms O -O2-aminomethyl-1,4-benzodioxane (33 g.) and3-cyclohexylsulphonyl-n-propyl chloride (22.45 g.) were heated at 150 C.for two hours prior to Working up as in Example 2. Drying under reducedpressure gave the crude hydrochloride (33.5 g.), melting point 171-175C.

Recrystallisation from ethanol gave the product as white crystals,melting point 173176 C.

Analysis.-Calculated for C H NSClO (percent): C, 55.46; H, 7.24; N,3.59. Found (percent): C, 55.66; H,

EXAMPLE 8 2- 3 '-tert-butylsulphonyl-n-propyl)aminoethyl-8-methyl-1,4-benzodioxane CH3 0 CHgNHCHgCH CHgS Ori -CH3 CHaH;

2-aminomethyl-8-methyl 1,4 benzodioxane (26.1 g.) and3-tert-b'utylsulphonyl-n-propyl chloride (14.9 g.) were heated at 150 C.for two hours and then worked up as in Example 1. Drying under reducedpressure gave the crude hydrochloride (24 g.), melting point 104-134 C.

. 7 Recrystallisation from isoprop yl alcohol gave the product as whitecrystals, melting point 147-151 C.

Analysis.-Calculated for C H NSClO (percent): C, 54.04; H, 7.47; N,3.71; S, 8.49; Cl, 9.38. Found (percent): C, 54.14; H, 7.38; N, 3.62; S,8.69; Cl, 9.62.

EXAMPLE 9 2-(3'-tert-amy1sulphonyl-n-propyl)aminomethyl-7-chloro-1,4-benzodioxane lnn 01 onmnomomomso p-omen.

EXAMPLE 2-(2-tert-amylsulphonylethyl) aminomethyl-1,4-benzodioxane CHNHCH CH SO CCH CHa 0 3 2-aminoethyl-1,4-benzodioxane (6.6 g.) andZ-tertamylsulphonyl ethyl chloride (4.0 g.) were heated at 155 C. fortwo hours and then worked up as in Exampie 1. Drying under reducedpressure gave the crude hydrochoride. Recrystallisation from isopropylalcohol gave the product as white crystals, melting point 186-187 C.Analysis-Calculated for C H ClNO S (percent): C, 52.80; H, 7.20; N,3.85; S, 8.81; Cl, 9.74. Found (percent): C, 52.45; H, 7.16; N, 3.85; S,8.64; Cl, 9.69.

EXAMPLE 11 Preparation of 2-(3-tert-amylsulphonyl-n-propyl)aminomethyl-8-methoxy-benzo-L4-dioxan (hydrochloride) A mixture of2-chloromethyl-8-methoxybenzo-1,4-dioxan (6.0 g., 0.03 mole) andtert-amylsulphonyl-n-propylamine (10.8 g., 0.06 mole) was heated at 150for 2 hours. The mixture was cooled, a solution of sodium hydroxide (2.4g., 0.06 mole) in water (30 ml.) was added and the mixture was extractedwith chloroform (3x30 1111.). The solvent was removed by distillationunder reduced pressure and unchanged amine was distilled ofi at 130-150"at 0.5 mm. Hg. The residue was subjected to chromatography on alumina(i) eluting with chloroform (ii) eluting with ethanol 8 Hydrochloric.acid (8 ml., 50%) was added 'to the appropriate fractionand the mixturerefluxed for 0.5 hr. The mixture was cooled and extracted withchloroform. Anhydrous ether was added to the extract when an oilseparated out. This oil was dried overnight in vacuo over phosphoruspentoxide when crystallisation occurred. The solid was recrystallisedtwice from ethylacetate/ether.

Weight-2,00 mg, m. 147-150 Calculated for (percent): C, 53.00; H, 7.41;N, 3.43; 7.85; Cl, 8.68. Found (percent): C, 52.54; H, 7.23; 3.67; S,7.53; Cl, 9.01.

Weclaim: 1. Basically 2-'substituted 1,4-benzodioxane having theformula: i

where Ris hydrogen, halogen having an atomic number not exceeding 35 oralkyljor alkoxy having from one tosix carand pharmacologicallyacceptable acid addition salts of such benzodioxane.

2. Basically Z-substituted 1,4-benzodioxane as claimed in claim 1,wherein R is hydrogen, 7- or 8-chlorine or 7- or S-methyl, -ethyl,'-methoxy or -ethoxy.

3. Basically Z-substituted 1,4-benzodioxane as claimed in claim 1,wherein R isa straight chain or branched chain alkyl having from 2 to 6carbon atoms or cyclohexyl.

4. Basically 2-substituted 1,4-benzodioxane as claimed in claim '3,wherein R is tertiary-butyl or tertiary amyl.

5. Basically 2-substituted1,4-benzodioxane as claimed in claiml, whereinn is 2,3 or 4.

6. 2-[(3' tertiary amylsulphonyl n propyl)aminomethyl]-1,4-benzodioxane.

References Cited UNITED STATES PATENTS 2,887,484 5/1959 Funke 260340.33,170,933 2/1965 Schmidt 260340.3 3,438,992 4/1969 Shen et al. 260-340.}X

OTHER REFERENCES Dunbar et al.: Chemical Abstracts, vol. 52 (1958), col.9134d.

ALEX MAZEL, Primary Examiner J. H. TURNIPSEED, Assistant Examiner U.S.Cl. X.R. 424-278

